To mount an optimum immune response, mature B lymphocytes undergo two genetic alterations in the forms of class switch recombination (CSR) and somatic hypermutation (SHM). CSR leads to the production of antibodies of various isotypes (IgG, IgE, IgA) while SHM results in the generation of antibody molecules with a much higher affinity for antigens. The B cell specific protein AID (activation induced deaminase) is essential to both processes. AID initiates CSR and SHM by deaminating cytidines within transcribed regions of the immunoglobulin locus. These lesions are then converted into point mutations during SHM or into DNA double strand breaks that serve as obligatory intermediates during CSR. Inactivation of AID leads to human immunodeficiency syndromes (Hyper-IgM2) where patients suffer from profound susceptibility to bacterial infections. On the other hand, deregulation of AID converts it into a general mutator and leads to mutations and translocations of oncogenes that have been implicated in mature B cell lymphomagenesis. An understanding of the processes that regulate AID activity is thus of utmost importance. The overall objective of this research proposal is to elucidate the mechanism by which AID activity is regulated during CSR and SHM. Recent studies have shown that protein kinase A (PKA) phosphorylates AID in vitro to activate its ability to bind its cofactor, the single-stand DNA binding protein Replication Protein A and mediate deamination of transcribed DNA substrates. To elucidate the role of AID phosphorylation in vivo, mice with a mutation in the AID phosphorylation site will be generated and analyzed for CSR and SHM. The mutant mouse will also be used in cellular and biochemical assays to delineate the function of phosphorylated AID in CSR and SHM. Finally, existing PKA mutants will be analyzed to test the hypothesis that AID phosphorylation by PKA is itself a highly regulated event and could potentially contribute to AID target specificity. Successful completion of the projects outlined in this proposal will provide mechanistic insights into reactions central to immunity and how aberrations in such physiological reactions can cause mature B cell tumors.
B cell lymphomas are the most common human malignancies. It is now clear that a large majority of B cell tumors arise due to mistargeted AID activity. Experiments proposed here will elucidate the role of AID in both immunity and cancer.
|Zheng, Simin; Kusnadi, Anthony; Choi, Jee Eun et al. (2018) NME proteins regulate class switch recombination. FEBS Lett :|
|Chen, Chun-Chin; Kass, Elizabeth M; Yen, Wei-Feng et al. (2017) ATM loss leads to synthetic lethality in BRCA1 BRCT mutant mice associated with exacerbated defects in homology-directed repair. Proc Natl Acad Sci U S A 114:7665-7670|
|Yen, Wei-Feng; Chaudhry, Ashutosh; Vaidyanathan, Bharat et al. (2017) BRCT-domain protein BRIT1 influences class switch recombination. Proc Natl Acad Sci U S A :|
|Vaidyanathan, Bharat; Chaudhry, Ashutosh; Yewdell, William T et al. (2017) The aryl hydrocarbon receptor controls cell-fate decisions in B cells. J Exp Med 214:197-208|
|Drané, Pascal; Brault, Marie-Eve; Cui, Gaofeng et al. (2017) TIRR regulates 53BP1 by masking its histone methyl-lysine binding function. Nature 543:211-216|
|Kunimoto, Hiroyoshi; McKenney, Anna Sophia; Meydan, Cem et al. (2017) Aid is a key regulator of myeloid/erythroid differentiation and DNA methylation in hematopoietic stem/progenitor cells. Blood 129:1779-1790|
|Yewdell, William T; Chaudhuri, Jayanta (2017) A transcriptional serenAID: the role of noncoding RNAs in class switch recombination. Int Immunol 29:183-196|
|DiMenna, Lauren J; Yen, Wei-Feng; Nicolas, Laura et al. (2017) Cutting Edge: The Transcription Factor Sox2 Regulates AID Expression in Class-Switched B Cells. J Immunol 198:2244-2248|
|DiMenna, Lauren J; Chaudhuri, Jayanta (2016) Regulating infidelity: RNA-mediated recruitment of AID to DNA during class switch recombination. Eur J Immunol 46:523-30|
|Balestrini, Alessia; Nicolas, Laura; Yang-Lott, Katherine et al. (2016) Defining ATM-Independent Functions of the Mre11 Complex with a Novel Mouse Model. Mol Cancer Res 14:185-95|
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